Reprogrammed Natural Killer Cells Attack Solid Tumors in Mouse Study

Cell therapies that harness the immune system have transformed treatment for some blood and lymphatic cancers, but solid tumors are far harder to treat: immune cells struggle to enter them, and tumors can weaken nearby immune defenses. Stanford Medicine researchers have developed a strategy to overcome this by transforming natural killer (NK) cells, immune cells known for rapidly attacking abnormal cells, into a specialized "tissue-resident" form that infiltrates solid tumors and destroys cancer cells.

In mouse experiments, the modified NK cells slowed the growth of several solid tumors, with a stronger effect when paired with an antibody that helps guide NK cells toward cancer cells. The study, led by senior author John Sunwoo, MD, was published last month in the journal Science Translational Medicine. Because NK cells do not typically trigger an immune reaction between people, such a treatment could be manufactured in large batches, frozen and made available to many patients, unlike therapies made from a patient's own cells. "It would be almost an off-the-shelf drug," Sunwoo said.

NK cells, first identified in the 1970s, recognize and destroy abnormal cells, including cancer and virus-infected cells, without needing to encounter a specific target beforehand. Some settle inside tissues such as the skin, lungs and liver instead of circulating in blood; past studies gave conflicting results, finding these tissue-resident NK cells either weak killers that suppress immune activity or highly effective. Cancer treatment requires the more aggressive type.

Sunwoo's team isolated circulating NK cells from blood donors and tested combinations of cellular signals. The key ingredient was TGF-beta (transforming growth factor beta), a signaling protein made by many cell types, including tumor cells. Just enough TGF-beta produced tissue-resident NK cells with strong tumor-killing activity, while too much left them dysfunctional and unable to kill. Briefly exposing the cells to short-lived tumor cells, which gave a burst of TGF-beta, produced the best killers; direct contact with the tumor cells was also essential.